The present invention relates to a method for the treatment or prevention of diseases mediated by the alpha-2B-adrenoceptor in mammals, by administering to said mammal a selective alpha-2B-adrenoceptor antagonist.
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
The selective alpha-2B-adrenoceptor antagonists shown in Scheme I below are all previously known. The inventors obtained the compounds A (ordering No AE-848/34956037), C (ordering No AF-399/36012031) and D (ordering No AH-034/34347043) from SPECS and BioSPECS B.V., Fleminglaan 16, 2289 C P Rijswijk, The Netherlands. The compounds B (ordering No 653716) and E (ordering No 569063) were supplied by ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego Calif. 92127.
It is known that alpha-2B-adrenoceptors mediate vascular contractions. Therefore, alpha-2B-antagonists are useful in the treatment or prevention of diseases involving vascular contraction. It has also been found that there is a genetic polymorphism in the alpha-2B-adrenoceptor gene at certain individuals. It has been observed that the alpha-2B-adrenoceptor protein at some subjects has a deletion of 3 glutamates from the glutamic acid repeat element of 12 glutamates (amino acids 297-309), in an acid trech of 17 amino acids, located in the third intracellular loop of the receptor polypeptide (Heinonen et al., 1999).
It has now been found that the compounds selected from the group consisting of compound A, B, C, D and E, the formulae of which are disclosed in Scheme I, are selective alpha-2B-adrenoceptor antagonists.
Thus, this invention relates to a method for the treatment or prevention of a disease mediated by the alpba-2B-adrenoceptor in a mammal, said method comprising administering to said mammal an effective amount of a selective alpha-2B-adrenoceptor antagonist, wherein said antagonist is a compotmd selected from the group consisting of compound A, B, C, D and E disclosed in Scheme 1, or a pharmaceutically acceptable salt of said compound.
Alpha-2B-adrenoceptor antagonists are useful in the treatment and/or prevention of many diseases.
Individuals having a deletion in the alpha-2B-adrenocepter protein (Heinonen et al., 1999), particularly the deletion/deletion genotype (D/D genotype) is an important target group which benefits from administration of selective alpha-2B-adrenoceptor antagonists.
It has been found that in a population-based cohort of Finnish middle-aged men that subjects with a D/D genotype of the alpha-2B-adrenoceptor gene have a significantly elevated risk for acute myocardial infarction (AMI) in a five-year follow-up study. The risk for AMI was increased in subjects who had no previously diagnosed coronary heart disease (CHD) at the study outset. Therefore, it has been postulated that the D/D genotype is related to an impaired capacity to down-regulate alpha-2B-adrenoceptor function during sustained receptor activation. Therefore, alpha-2B-adrenoceptors are believed to be involved in the pathogenesis of a significant fraction of all cases of AMI, especially in subjects with the D/D genotype, but also in I/D and I/I subjects (I means xe2x80x9cinsertionxe2x80x9d and stands for the xe2x80x9cnormalxe2x80x9d allele).
The alpha-2B-adrenoceptor antagonists as disclosed in this invention would be particulaly useful in the treatment or prevention of coronary heart diseases. As examples can be mentioned.
a) Acute AMI
If alpha-2B-adrenoceptor dependent vasoconstriction is a causative factor in some cases of AMI, then antagonism of these receptors should restore coronary circulation and reduce the ischemic myocardial damage.
b) Unstable Angina Pectolis
An alpha-2B-adrenoceptor antagonist will relieve the vasoconstrictive component in the sustained ischemic episode, thus alleviating the symptoms and preventing AMI.
c) Prinzietal""s Variant Form of Angina Pectoris
Vasoconstriction is a key factor in the pathogenesis of Prinzmetal""s angina, and an alpha-2B-adrenoceptor antagonist may resolve and prevent attacks.
d) Other Forms of Chronic Angina Pectoris and CHD
An alpha-2B-adrenoceptor antagonist will help to alleviate the vasoconstrictive component in all types of CHD, providing both symptomatic relief and protection from AMI. A general reduction in vascular tone will contribute to this by reducing venous return, cardiac workload and oxygen consumption (a nitrate-type effect; see below).
e) Prevention of Restenosis After Coroary Angioplasty in Cases where Vasoconstriction Plays a Role in Restenosis
Furhennore, the alpha-2B-adrenoceptor antagonists as disclosed in this invention would be useful in the treatment or prevention of essential hypertension, especially in subjects with increased sympathetic activity and a hyperdynamic circulatory system.
In the study mentioned above, the D/D variant of the alpha-2B-adrenoceptor gene was not clearly associated with blood pressure. The inventors believe that this was due to two main factors, 1) antihypertensive treatment, and 2) complex regulation of systemic blood pressure. In another study (Heinonen et al.), it was observed that the D/D genotype was associated with reduced basal metabolic rate and reduced heart rate. These associations probably reflect increased vascular resistance in these subjects.
In transgenic mice with targeted inactivation of the alpha-2B-adrenoceptor gene, intravenously administered alpha-2-adrenoceptor agollists fail to induce the characteristic blood pressure elevation which is seen in normal animals and also in humans after large doses of such drugs (Link et al., 1996). The hypotensive effect of these drugs was markedly accentuated. This demonstrates that alpha-2B-adrenoceptors mediate vascular contraction. Thus, an antagonist should reduce blood pressure. This effect has not been seen with alpha-2B-nonselective alpha-2-adrenoceptor antagonists, because antagonism of alpha-2A-adrenoceptors increases sympathetic outflow, cardiac output and blood pressure. In mice with dysfunctional alpha-2A-adrenioceptors, alpha-2-adreoceptor agonists caused an accentuated hypertensive response and no hypotension (MacMillan et al., 1996).
An alpha-2B-adrenoceptor antagonist is postulated to have favourable effects in hypertensive subjects through their effects on renal function, muscle blood flow, and also on vascular resistance in other vascular beds. The anti-AMI effect of such a drug will be an additional benefit, as hypertension is a significant risk factor for AMI. This protection is due to thuee factors: 1) a reduction in systemic blood pressure, 2) decreased risk of coronary vasoconstiction, and 3) a nitrate-like effect on venous return, myocardial workload and oxygen consumption.
Moreover, the alpha-2B-adrenoceptor antagonists as disclosed in this invention would be useful in the treatment or prevention of other vascular diseases. Specifically, benefits can be expected in the treatment or prevention of
vasoconstriction and hypoxic brain damage subsequent to subarachnoid haemorrhage,
migraine,
Raynaud""s disease and cold intolerance,
pre-eclampsia,
male erectile dysfunction, and
obesity and the metabolic syndrome.
The last mentioned effect is due to the fact that reduced muscle blood flow and reduced basal metabolic rate contribute to the development of obesity and hypertension. An alpha-2B-adrenoceptor antagonist will, by increasing the muscle blood flow, increase energy expenditure and shift the caloric balance to a favourable direction.
The alpha-2B-adrenoceptor antagonists disclosed in this invention are also useful in anesthesia and analgesia to potentiate the clinical efficacy of alpha-2-adrenoceptor agonists which are not selective for the alpha-2B-adrenoceptor subtype. By blocking the vasoconstiiction induced by these agonists, a simultaneously administered alpha-2B-adrenoceptor antagonist will allow the use of larger doses of said agonists, up to anesthetic dose levels which have not previously been possible in man, only in veteinary anesthetic practice.